3-substituted-4-aryl isoquinolines

ABSTRACT

3-Substituted-4-aryl isoquinolines, e.g. 3-tertiary butyl-4phenyl-1,2,3,4-tetrahydroisoquinoline, prepared from corresponding isoquinoline intermediates, are useful as antidiabetic agents.

United States Patent Houlihan et a1.

3-SUBSTlTUTED-4-ARYL ISOQUINOLINES Inventors: William J. l-loulihan, Mountain Lakes; Jeffrey Nadelson, Lake Parsippany, both of NJ.

Assignee: Sandoz-Wander, Inc., Hanover, NJ.

Filed: Oct. 30, 1973 Appl. No: 411,074

Related US. Application Data Continuation-impart of Ser. No. 339,616, March 3, 1973, abandoned, which is a continuation'in-part of Ser. No. 259,860, June 5, 1972, abandoned.

US. CL... 260/283 R, 260/283 SY, 260/286 R, 260/289 R, 260/343.3, 260/515 R, 260/521 R,

lint. C1 C07d 33/34 Field of Search ..260/283 R, 289 R 1 Mar. 18, 1975 I 56] References Cited UNITED STATES PATENTS 3,666,763 5/1972 Grethe et a1. 260/289 R 3,745,162 7/1973 Helsley 260/289 R 3,753,994 8/1973 Diana 260/289 R OTHER PUBLICATIONS Gardent et 211., Chemical Abstracts, Vol. 64, 1966, p.

Primary E,\'an1inerDona1d Gv Daus Assistant Eranu'ncr-Mary C. Vaughn Attorney, Agent, or Firn1Gera1d D. Sharkin; Robert S. Honor 1 S-SUBSTITUTED- i-ARYL ISOQUINOLINES This application is a continuation-in-part of application Ser. No. 339,6l6, filed Mar. 3, 1973 now abandoned, which in turn is a continuation-in-part of application Ser. No. 259,860, filed June 5, 1972 now abandoned.

This invention pertains to 3-substituted-4-aryl R (I) where R, represents la where R and R are each independently methyl or ethyl, or

R and R together represent (Cl-l where n represents 4, 5, or 6, and

R R R and R each independently represent hydrogen, halo of atomic weight 19-36, trifluoromethyl, lower alkyl, ie. alkyl of 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, and the like, and lower alkoxy, ie., alkoxy having 1-4 carbon atoms, such as methoxy, ethoxy. isopropoxy, and the like, provided that R,, and R may not represent alkyl at the 8-position, and provided further that two trifluoromethyl groups or two tert.butyl groups or a trifluoro methyl and a tertiary butyl group are not on adjacent carbon atoms.

The compounds of formula (I) are prepared by hydrogenation of corresponding isoquinoline intermediates of formula (ll) according to the following reaction scheme:

where R through R, and the provisos are as set out above.

Compounds (ll) may be converted into compounds (I) by hydrogenating the former with a platinum metal catalyst, such as platinum oxide in inert solvent, such as loweralkanoic acid, e.g., acetic acid, at a temperature of from about 2060C., preferably about 35C., at 25-100 psi until about two equivalents of hydrogen are absorbed. Neither time temperature of reaction, pressure nor the solvent used is critical. The

compounds of formula (I 1) represent an additional aspect of this invention and they may be prepared according to the following reaction scheme:

X Br R7 N N Rum Re i l I R4 @114 (III) (II) where R, through R, and the provisos are as set out above, and

X represents halo of atomic weight about 35-80.

Compounds (11) may be prepared from compounds (III) by hydrogenating the latter at 25-100 p.s.i. in inert alcohol solvent, e.g., lower alkanols such as ethanol or isopropanol in the presence of platinum metal catalyst such as palladium, conveniently palladium on carbon, until one equivalent of hydrogen is absorbed. The hydrogenation may be performed at a temperature of about 2060C., preferably about 2535C. A base such as an alkali metal hydroxide, e.g. sodium hydroxide or potassium hydroxide, is desirably added to neutralize the HCl liberated in the reaction. Neither the time, temperature, pressure nor solvent utilized is criti' cal in obtaining compounds (II).

The novel compounds of formula (11]) may be obtained according to the following reaction scheme:

0 X R1 R1 /l\ NH N Re Rom I I R1 \l/Ri (IV) (III) where X, R through R and the provisos are as set out above.

Compounds (III) are accordingly obtained by treating a compound of formula (IV) with halogenating agent such as PCl POCl SOCl PBr PBr and SOBr and the like optionally in solvent such as aromatic hydrocarbon solvent, e.g., benzene or toluene, for about 30-90 minutes at a temperature of about -150C., conveniently at the reflux temperature of the system. Neither time, temperature nor solvent are critical.

The compounds (IV) are also novel and may be prepared according to the following reaction scheme:

0 CH3 0 NBA) on I] l /\NII R6 O Rt I R5 (V) R5 (IV) 3 4 Where by treatment with a lithiating agent, particularly an R through R, and respecting compounds (IV) the alkyl or aryl lithium compound; n-butyl lithium is espeprovisos are as set out above, and provided further cially preferred. This reaction may be performed in solthat R and R may not represent alkyl at a position vent and for a period of time similar to that described ortho to the carbon bonded to the amido group on above in connection with the process for obtaining compounds (V), provided further that two trifluocompounds (V). The temperature of the reaction is romethyl groups or two tert.butyl groups or a triflu preferably from about l0 to +l0C. Compound (VI) oromethyl and a tertiary butyl group are not on adis normally not isolated from the reaction mixture and jacent carbon atoms. may be used directly in the process for preparing com- Compounds (IV) are thus prepared from compounds 10 POu d above- (V) by treating the latter with polyphosphoric acid at The compounds (VIII) are preparable from coma temperature of about 70l20C., preferably about Pounds of the formula 80-lOOC., for about one-half to 3 hours. The reaction 0 time and temperature are not critical. 1 I

As will be appreciated by persons skilled in the art, 0 compounds (IV) and (V) may also exist in tautomeric R6 I H form and the exact form of the compounds and the amount of compound in each tautomeric form will depend upon such factors as pH, temperature, solvent, etc. For simplicity, compounds (IV) and (V) will be depicted by use of the structures shown, but it will be understood that the corresponding tautomeric forms and R5 (IX) their use and production are also contemplated by the V invention. where R, through R, are as set out above, provided that The compounds of formula (V) may be obtained ac- 7 R and R may not represent alkyl at a position ortho cording to the following reaction scheme from comto the carbon bonded to the acid group, and provided pounds (VI) and compounds (VII). further that two trifluoromethyl groups or two tertiary RT 0 Li CH; v11

N om R7 0 CH3 R4 (VI) R5 where butyl groups or a trifluoromethyl and a tertiary butyl R, through R, and the provisos are as set out above group are not on adjacent carbon atoms, in a standard regarding compounds (V), and manner by halogenating compounds (IX) with haloge- Y represents halo of atomic weight -80. nating agents such as thionyl chloride, and aminating Compounds (VI) and (VII) are first reacted in inert the resulting acid halide with tert.butylamine.

solvent such as hydrocarbon solvents, e.g. benzene or The compounds (IX) are prepared according to the toluene, or ethers such as ethyl ether or tetrahydrofollowing reaction scheme: furan, at a temperature of from about 60 to about O O 10C. The preferred temperature range is about -20 R1 1| R1 A to 50C. and the reaction may be run for l-lO hours.

OH The resulting product IS then hydrolyzed by convenl 0 tional techniques to provide compounds (V). X \T/ The compounds of formula (VI) may be obtained from the compounds of the formula I 0 CH5 R4 R4 R7 A X\ NH --oHi (in, (X) R5 1x) I R5 l where R, through R, and the provisos for compounds (IX) are as set out above, provided that R, and R on compounds (X) may not represent alkyl at the 7- R4 position, and provided further that two trifluoromethyl groups or two tertiary butyl groups or a trifluoromethyl R, (VIII) and a tertiary butyl group are not on adjacent carbon atoms. Where Compounds (IX) are prepared from compounds (X) R R R R, and the provisos are as set out above by hydrogenating the latter with hydrogen gas in the for compounds (V), presence ofa platinum metal catalyst, preferably palladium on carbon. The hydrogenation is conveniently Certain of the compounds of formulae (V11), (X11) performed in alcoholic solvents at room temperature. and (X111) are known and may be prepared according Compounds (X) may be prepared ccordi g o th to methods disclosed according to the literature. The

following reaction scheme: compounds of formulae (VII), (XII) and (XIII) not a R o T /u\ V 7 ll-[R A R6 R5 l 0 R i' 1, 1 t

(XI) R (x) '5 5 where specifically disclosed may be prepared by methods 0 represents lower y as defined abOVe, Or ph analogous to those in the literature from known comny pounds. and Compounds (I) and ([1) may exist in the form of their R through R, are as set out above, as are the provisos acid addition salts. Said salts and their respective free respecting compounds (X), and provided that rebases may be converted from one to the other by congarding compounds (XI) R and R do not repreventional techniques and are chemically interchangesent alkyl at a position ortho to the carbon bonded able for purposes of the above described process. The to the amido group, and provided further that two compounds of formula (I) exist in racemic form or in trifluoromethyl groups or two tertiary butyl groups the form of optically active isomers. The separation or a trifluoromethyl and a tertiary butyl group are and recovery of the respective isomers may be readily not on adjacent carbon atoms. accomplished employing conventional techniques, and

co ng to the above process, compound (XI) is such isomers are included within the scope of the inheated in inert hydrocarbon or halogenated hydrocaren bon solvent, e.g., benzene, toluene, pentane. o- The p un of formula above are Useful dichlorobenzene and the like. The reaction may be carcause they possess pharmacological properties in aniried out at a temperature of about 80-200C., and mals, such as mammals. In particular, the compounds conveniently at the reflux temperature of the solvent may be used as anti-diabetic agents as indicated by uiililedtheir activity in rats orally administered active agent at The compounds of formula (XI) are obtainable from a dose of 200 mg/kg of animal body weight. The rats compounds (X11) according to the following reaction are made diabetic by intraperitoneal injection of 250 scheme: mg/kg of alloxan monohydrate four days prior to the NER ( lithiation (2) aldehyde (x11) (XIII) i Rh where R, through R R and the provisos are as set out experiment. Only those rats showing positive reactions above for compounds (X1). for sugar in urine are used. The positive reactions are Compounds (XI) are prepared from compounds as shown on C1inistix made by Ames Company,Div1- (XII) in inert hydrocarbon or ether solvent, e.g., bension of Miles Laboratories, Inc., Elkhart. Ind. and dezene, toluene, ethyl ether, tetrahydrofuran and the like. scribed in US. Pat. Nos. 3,453,180; 3,164,534; The reaction is a two step reaction involving lithiation 3,123,443; 3,050,373 and 2,981,606.

ofthe compound (XII) to obtain a dilithio intermediate Two hours after oral administration of the drug, the thereof, which in turn is treated with an appropriately rats are anesthetized by intraperitoneal injection of sosubstituted benzaldehyde (XIII) to obtain compounds dium hexobarbital (1 g/ g)- Blood is taken y inci- (XI). The lithiation is preferably performed at a temsion of the jugular vein and is collected in a test tube perature between about 60 to +10C. for about 1-3 which contains 0.1 ml. of heparin 1 ,000 units/ml). The hours whereas the second step, generally performed heparinized blood is used to determine blood sugar without separation of the dilithio intermediate, is perl e fOrmed between -l0 and +10C. for about 1-3 hours. Anti-diabetic activity is determined by comparison of Unless specifically indicated otherwise, the products the mean blood sugar (mg of drug treated rats with of each of the reactions described above may be recovthat of controls (given vehicle two hours before sacriered by conventional techniques such as crystalization, ficing).

filtration, trituration, and the like. For such usage, the compounds of formula (1) may 7 be combined with a pharmaceutically acceptable carrier or adjuvant, and may be administered orally in such forms as tablets, capsules, clixers, suspensions and the like, or parenterally in the form of an injectable solution or suspension. The dosage will vary depending upon the mode of administration utilized and the particular compound employed.

As indicated above, the compounds of formula (I) may be similarly administered in the form of their nontoxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared by reacting the base with an appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral salts, such as hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate and the like.

As noted above, the compounds of formula (I) exist as optical isomers. In some cases, greater pharmacological activity or other beneficial attribute may be found for a particular isomer and in such instances administration of such isomer may be preferred.

In general, satisfactory results are obtained when the compounds (I) are administered at a daily dosage of from about 4-400 mg/kg of animal body weight, preferably orally and in divided doses, 2 to 4 times a day or in sustained release form. For most larger mammals (e.g. primates) the total daily dosage is from about 2502,000 mg. per day. Dosage forms suitable for internal use comprises from about 60 mg. to about 1,000 mg. of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

Tablets containing 100 mg. of active ingredient and 250 mg. of lactose may be prepared by conventional techniques and are useful in treating diabetes at a dose of one tablet 2 to 4 times a day.

EXAMI LE 1.

N-tert.butyl-a-phenyl-o-toluamide To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 67.5 g. (0.5 mole) N-methyl benzamide and 1,200 ml. dry tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5C. Stirring is initiated and 688 ml. of 1.6 M. n-butyl lithium (-l.l mole) in hexane is added dropwise over about 1 hour maintaining temperature below 8C. The resulting dilithio salt is stirred at 5C. for an additional hour and then a solution of 58.5 g. (0.55 mole) of benzaldehyde in 500 ml. tetrahydrofuran is added dropwise in about 1 hour maintaining the temperature between -l0 to +10C. The resulting mixture is stirred at 5C. for 1 hour longer and 300 ml. of saturated ammonium chloride is added maintaining the temperature at about l0C. The layers are separated and the organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a-hydroxy-N-methyl-aphenyl-o-toluamide.

A mixture of 76.5 g. of a-hydroxy-N-methyl-a-phenyl-o-toluamide and (0.3 l4 mole) 150 ml. 0- dichlorobenzene is heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting solid triturated with cold ether to give 3-phenyl phthalide.

When the above process is carried out and in place of benzaldehyde there is used a. p-chlorobenzaledhyde,

b. o-tolualdehyde.

c. p-methoxybenzaldehyde,

d. m-trifluoronietliylbenzaldehydc,

e. 3,4'dichlorobenzaldehyde, or

f. p-tolualdehyde there is obtained through the corresponding intermediate a-hydroxy-N-methyl-o-toluamide,

a. 3-p-chlorophenyl phthalide,

b. 3-o-tolyl phthalide.

. 3-p-methoxyphenyl phthalide. 3-m-trifluoromethylphenyl phthalide, 3-(3.4-dichlorophcnyl) phthalide, or

f. 3-p-tolyl phthalide, respectively.

When the above detailed procedure is carried out and in place of N-methyl benzamide there is used g. o-chloro-N-phenyl benzamide,

h. N-methyl-p-toluamide,

i. N-methyl-m-trifluoromethyl benzamide, or

j. p-methoxy-N-methyl benzamide, there is obtained through the corresponding intermediate a-hydroxy-a-phenyl-o-toluamide,

g. 7-chloro-3-phenyl phthalide,

h. 5-methyl-3-phenyl phthalide,

i. 6-trifluoromethyl-3-phenyl phthalide, or

j. 5-methoxy-3-phenyl phthalide, respectively.

A mixture of 55.2 g. of 3-phenyl phthalide (0.263 mole), 600 ml. ethanol and 5.9 g. of 10% Pd/C is hydrogenated at room temperature and 50 psi until 1 equivalent of H is absorbed. The catalyst is removed by filtration and the solvent removed in vacuo and the residue triturated in petroleum ether to give oz-phenylo-toluic acid; m.p. l0l--l04C.

To a mixture of 49.8 g. (0.235 mole) a-phenyl-otoluic acid, 300 ml. ether and 10 ml. pyridine, add dropwise with stirring 25 ml. (0.35 mole) of thionyl chloride. The resulting mixture is stirred 21 hours at room temperature then filtered and the solvent removed in vacuo. The resulting acid chloride is dissolved in 150 ml. ether and added dropwise to 35.7 g (0.48 mole) of tert.butylamine in 500 ml. of ethyl ether, and the mixture cooled to 0C. After addition is complete the resulting mixture is stirred 1 hour at room temperature, the layers separated, the ether washed with ml. of water, 100 ml. of 2N sodium hydroxide and then with water again, dried over magnesium sulfate, filtered and evaporated to give N-tert. butyl-a-phenyl-o-toluamide; m.p. 9l-92C.

When the procedure described in the above two paragraphs is carried out and in place of 3-phenyl phthalide there is used can EXAMPLE 2.

N-tert.butyl-a-phenyl-a-pivaloyl-o-toluamide To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube and maintained under a nitrogen atmosphere there is added at room temperature 59 g. (0.221 mole) of N-tert.butyl-a-phenyl-otoluamide in 1,000 ml. dry tetrahydrofuran. The flask is immersed in an ice bath and cooled to an internal temperature of C. Stirring is initiated and 3365 ml. (0.490 mole) of n-butyl lithium in hexane) is added dropwise in about 1 hour maintaining the temperature below 8C. The resulting solution is stirred 2 hours at room temperature, cooled to 5C., and 26.6 g. (0.221 mole) of pivaloyl chloride in 250 ml. of dry tetrahydrofuran is added dropwise maintaining tempera-- ture below 8C. After addition, the mixture is stirred 2 hours at room temperature and hydrolyzed with 150 ml. of saturated ammonium chloride, the resulting solution is filtered and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether to give N-tert.butyl-a-phenyl-a-pivaloyl-otoluamide; m.p. l57-16lC.

When the above process is carried out and in place of N-tert.butyl-a-phenyl-o-toluamide there is used a. a-(p-chlorophenyl)-N-tert.butyl-o-toluamide.

b. N-terLbutyl-a-(o-tolyl)-o-toluamide,

c. a (p-methoxyphenyl)-N-Tert.butyl-o-toluamide,

d. Ntert.butyl-a-(m-trifluoromethylphenyl)-otoluamide,

e. a-(3,4dichlorophenyl)-N-terLbutyl-o-toluamide,

f. N-tert.butyl-oz-(p-tolyl)-o-toluamide.

g. 6-chloro-N-tert.butyl-oz-phenyl-o-toluamide,

h. N-tert.butyl-4-methyl-a-phenyl-o-toluamide,

i. N-tert.butyl-a-phenyl-5-trifluoromethyl-otoluamide, or

j. 4-methoxy-N-tert.butyl-a-phenyl-o-toluamide, there is obtained a. a-(p-chlorophenyl)-N-tert.butyl-a-pivaloyl-otoluamide,

b. N-tert.butyl-a-pivaloyl-a-(o-tolyl)-o-toluamide,

c. a-(p-methoxyphenyl)-a-pivaloyl-N-tert.butyl-otoluamide,

d. N-tert.butyl-a-pivaloyl-a-(m-trifluoromethylphenyl)-o-toluamide,

e. a-(3.4-dichlorophenyl)-Ntert.butyl-a-pivaloyl-otoluamide.

g. o-cliloro-N-tert.butyl-wpivaloyl-a-phenyl-otoluamidc.

h. N-tert.butyl-4-methyl-a-pivaloyl-a-phenyl-otoluamide,

i. N-tert.butyl-a-pivaloyl-a-phenyl-5-trifluoromethylo-toluamide, or

j. 4-methoxy-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide. respectively.

When the above process is carried out and in place of pivaloyl chloride there is used 2,2-dimethylbutanol chloride or l-methyl cyclohexanecarbonylbromide, there is obtained k. a-(2,2-dimethylbutanoyl)-N-tert.butyl-a-phenylo-toluamide, or

10 l. N-tert.but 'l-a-( l-methyl cyclohexanoyl)-a-phcnylo-toluamiderespectively.

EXAMPLE 3.

3-tert.butyl-4-phenyl isocarbostyril ln portions 79 g. (0.225 mole) of N-tert.but \'l-aphenyl-oz-pivaloyl-o-toluamide is added to l,l3t) mg. of

polyphosphoric acid heated to C. The mixture is stirred 1 hours at 90C. and poured onto ice with stirring. The resulting solid is filtered and washed thoroughly with water. The solid is recrystallized from chloroform: ethyl ether (1:1) to give 3-tert.butyl-4-phenylisocarbostyril; m.p. 284286C.

When the above process is carried out and in place of N-tert.butyLa-phenyl-a-pivaloyl-o-toluamide there is used a. a-(p-chlorophenyl)-N-tert.butyl-a-pivaloyl-otoluamide,

b. N-tert.butyl-a-pival0yl-a-(o-tolyl)-o-toluamide,

c. a-(p-methoxyphenyl)-a-pivaloyl-N-tert.butylotoluamide,

d. N-tert.butyl-a-pivaloyl-oz-(mtrifluoromethylphenyl)-o-toluamide,

e. a-(3,4-dichlorophenyl)-N-tert.butyl-a-pivaloyl-otoluamide,

f. N-tert.butyl-a-pivaloyl-a-(p-tolyl)-o-toluamide,

g. 6-chloro-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide,

h. N-tert.butyl-4-methyl-oz-pivaloyl-a-phenyl-otoluamide,

i. N-tert.butyl-oz-pivaloyl-a-phenyl-S-trifluoromethylo-toluamide, or

j. 4-methoxy-N-tert.butyl-a-pivaloyl-a-phenyl-otoluamide.

k. a-(2.2-dimethylbutanoyl)-N-tert.butyl-a-phenylo-toluamide.

l. N-tert.butyl-a-( l-methyl cyclohexanoyU-a-phenylo-toluamide,

.there is obtained EXAMPLE 4 3-tert.butyl-l-chloro-4-phenyl isoquinoline A mixture of 11 g. (0.04 mole) of 3-tert. butyl-4- phenyl isocarbostyril and 40 ml. of phosphorous oxychloride is refluxed for 1 hour. The excess solvent is re moved in vacuo and ice is added to the residue and stirred. The resulting solid is filtered and washed with water and recrystallized from ethanol to giv'e 3- tert.butyl-l-chloro-4-phenyl isoquinoline; mp. l39-l40C.

When the above process is carried out and in place of phosphorous oxychloride there is used phosphorous pentachloride or thionyl chloride, the identical product is again obtained.

When the above process is carried out and in place of 3-tert.butyl-4-phenyl isocarbostyril there is used a. 3-tert.butyl-4-(p-chloropheny) isocarbostril, b. 3-tert.butyl-4-(o-tolyl) isocarbostyril, c. 3-tert.butyl-4(p-methoxyphenyl) isocarbostril, d. 3-tert.butyl-4-(m-trifluoromethylphenyl) isocarbostyril, e. 3-tert.butyl-4-(3,4-dichlorophenyl) isocarbostyril, f. 3-tert.butyl-4-(p-tolyl) isocarbostyril, g. 3-tert.butyl-8-chloro-4-phenyl isocarbostyril, h. 3-tert.butyl-6-methyl-4-phenyl isocarbostyril, i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isocarbostyril, j. 3-tert.butyl-6-methoxy-4-phenyl isocarbostyril k. 3-(2.2-dimethylbutyl)-4-phenyl isocarbostyril. or I. 3-l( l-methyl cyclohexyl)-4-phenyl isocarbostyril. there is obtained a. 3-tert.butyl-l-chloro-4-(p-chlorophenyl) isoquinoline, b. 3-tert.butyl-l-chloro-4-(o-tolyl) isoquinoline, c. 3-tert.butyl-l-chloro-4-(p-methoxyphenyl) isoquinoline, d. 3-tert.butyl-1-chloro-4(m-trifluoromethylphenyl) isoquinoline, e. 3-tert.butyl-1-chloro-4-(3,4-dichlorophenyl) isoquinoline, f. 3-tert.butyl-1-chloro-4-(p-tolyl) isoquinoline, g. 3-tert.butyl-1,8-dichloro-4-phenyl isoquinoline, h. 3-tert.butyl-l-chloro-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyll -chloro-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-l-chloro-6-methoxy-4-phenyl isoquinoline,

k. 3-(2.2-dimethylbutyl)- l-chloro-4-phenyl isoquinoline, or

I. 3-(l-metliyleyelohexyl)-l-ehloro-4-phenyl isoquinoline, respectively.

EXAMPLE 5.

3-tert.butyl-4-phenyl isoquinoline hydrochloride A mixture of 21.7 g. (0.073 mole) of 3-tert.butyl-lchloro-4-phenyl isoquinoline, 4.09 g. (0.073 mole) ptassium hydroxide, 1.09g 10% palladium on carbon and 1 liter of ethanol is hydrogenated at room temperature and 50 psi until 1 equivalent of hydrogen is absorbed.

The catalyst is filtered off and washed with ethanol, combined ethanol portions are evaporated in vacuo. The residue is dissolved in ethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl. The resulting white solid is filtered and recrystallized from ethanolethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl. The resulting white solid is filtered and recrystallized from ethanol-ethyl ether lzl to give 3-tert.butyl- 4-phenyl isoquinoline hydrochloride; m.p. 236238C. When the above process is carried out and in place of 3-tert.butyl-l-chloro-4-phenyl isoquinoline there is used a. 3-tert.butyl-l-chloro-4-(p-chlorophenyl) isoquinoline. h. 3-tert.butyl-l-chloro-4-(o-tolyl) isoquinoline. c. 3 -tert.butyl-l-chloro-4-(p-methoxyphenyl) isoquinoline. d. 3-tert.butyl-l-chloro-4(m-trifluoromethylphenyl) isoquinoline.

12 e. 3-tert.butyl-l-chloro-4-(3,4-dichlorophenyl) isoquinoline, f. 3-tert.butyl-l-chloro-4-(p-to|yl) isoquinoline, g. 3-tert.butyl-l,8-dichloro-4-phenyl isoquinoline, 5 h. 3-tert.butyl-l-chloro-6-methyl-4-phenyl isoquinoline, i. 3-tert.butyl-l-chloro-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-l-chloro-6-methoxy-4-phenyl isoquinoline,

k. 3-(2,2-dimethylbutyl)-l-chloro-4-phenyl isoquinoline, or

l. 3-(l-methylcyclohexyl)-l-chloro-4-phenyl isoquinoline,

there is obtained as the hydrochloride a. 3-tert.butyl-4-(p-chlorophenyl) isoquinoline,

b. 3-tert.butyl-4-(o-tolyl) isoquinoline,

c. 3-tert.butyl-4-(p-methoxyphenyl) isoquinoline,

d. 3-tert.butyl-4-(m-trifluoromethylphenyl) isoquinoline,

e. 3-tert.butyl-4-(3,4-dichlorophenyl) isoquinoline,

f. 3-tert.butyl-4-(p-tolyl) isoquinoline,

g. 3-tert.butyl-8-chloro-4-phenyl isoquinoline,

h. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline, j. 3Ftert.butyl-6-methoxy-4-phenyl isoquinoline, k. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline, or l. 3-( l-methylcyclohexyl)-4-phenyl isoquinoline, re-

spectively.

' EXAMPLE 6.

3-tert.butyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline A mixture of 28.5 g. (0.11 mole) of 3-tert.butyl-4- phenyl isoquinoline, 2.85 g. platinum oxide and 300 ml. of acetic acid is hydrogenated at room temperature and 50 psi until two equivalents of hydrogen are absorbed. The catalyst is filtered off and the acetic acid is evaporated in vacuo. The residue is dissolved in ether, washed with 50% sodium hydroxide, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from petroleum ether to give 3-tert.butyl-4- phenyl-l,2,3,4-tetrahydroisoquinoline; m.p. 798lC.

When the above process is carried out and in place of 3-tert.butyl-4-phenyl isoquinoline there is used a. 3-tert.butyl-4-(p-chlorophenyl) isoquinoline.

b. 3-tert.butyl-4-(o-tolyl) isoquinoline,

c. 3-tert.butyl-4-(p-methoxyphenyl) isoquinoline,

d. 3-tert.butyl-4-(m-trifluoromethylphenyl) iso quinoline,

e. 3-tert.butyl-4-(3,4-dichlorophenyl) isoquinoline,

f. 3-tert.butyl-4-(p-tolyl) isoquinoline,

g. 3-tert.butyl-8-chloro-4-phenyl isoquinoline,

h. 3-tert.butyl-6-methyl-4-phenyl isoquinoline,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl isoquinoline,

j. 3-tert.butyl-6-methoxy-4-phenyl isoquinoline,

k. 3-(2,2-dimethylbutyl)-4-phenyl isoquinoline. or

I. 3-( l-methylcyclohexyl)-4-phenyl isoquinoline, there is obtained a. 3-tert.butyl-4-(p-chlorophenyl)-l2,3,4-

tetrahydroisoquinolinc,

3-tert.butyl-4-(o-tolyl)-l,2,3.4-

tetrahydroisoquinoline. c. 3-tert.butyl-4-(p-methoxyphenyl)- l .2,3.4-

tetrahydroisoquinoline, d. 3-tert.butyl-4-(m-trifluoromethylphenyl)-l2,3,4-

tetrahydroisoquinoline,

e. 3-tert.butyl-4-( 3 ,4-dichlorophenyl )-l ,2,3 ,4-

tetrahydroisoquinoline, f 3-tert.butyl-4-(p-tolyl)- l ,2,3 ,4-

tetrahydroisoquinoline,

. 2-tert.butyl-8-chloro-4-phenyl-l ,2,3 ,4-

tetrahydroisoquinoline,

h. 3-tert.butyl-6-methyl-4-phenyl-l ,2,3 ,4-

tetrahydroisoquinoline,

i. 3-tert.butyl-4-phenyl-7-trifluoromethyl-I ,2,3 ,4-

tetrahydroisoquinoline,

j. 3-tert.butyl-6-methoxy-4-phenyl-l ,2,3 ,4-

tetrahydroisoquinoline,

k. 3-(2,2'dimethylbutyl)-4-phenyl-l,2,3,4-

tetrahydroisoquinoline,

I. 3-( l-methylcyclohexyl)-4-phenyl-1,2,3,4-

tetrahydroisoquinoline, respectively.

The title compound of this example is an effective antidiabetic when orally administered to diabetic animal at a dosage of 100 mg. twice per day.

What is claimed is:

1. A compound of the formula where R represents r -(I]R2 where R and R are each, independently, methyl or ethyl,

or R and R together represent (CH 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is 3-tert.butyl-4-phenyl-1,2, 3,4-tetrahydroisoquinoline. 